In 2011, the surprising discovery was made that DHEA, as well as DHEA-S, directly bind to and activate the TrkA and p75NTR with high affinity.[3] DHEA was subsequently also found to bind to the TrkB andTrkC with high affinity, though it notably activated the TrkC but not the TrkB.[4] DHEA and DHEA-S bound to these receptors with affinities that were in the lownanomolar range (around 5 nM), although the affinities were nonetheless approximately two orders of magnitude lower relative to the highly potentpolypeptide neurotrophins (0.01–0.1 nM).[3][4] In any case, DHEA and DHEA-S were identified as important endogenousneurotrophic factors.[3] These findings may explain the positive association between decreased circulating DHEA levels with age and age-relatedneurodegenerative diseases.[2]
Subsequently, a series ofspiroderivatives of DHEA that had beensynthesized and assessed in 2009 as potentialneuroprotective agents was re-investigated.[1][2] Of these, BNN-20 was assayed and found to directly bind to and activate the TrkA, TrkB, and p75NTR.[2] In addition, it was found to cross theblood–brain barrier and to have strong neuroprotective effects ondopaminergicneuronsin vivo in amousemodel of dopaminergicneurodegeneration, which were dependent, at least in part, on activation of the TrkB.[2] Moreover, unlike DHEA, it lacked anyhormonal actions.[2] As such, BNN-20 was described as a BDNF mimetic and was proposed as a potential novel treatment for Parkinson's disease and other conditions, particularly of the neurodegenerative variety, likeamyotrophic lateral sclerosis.[2][5]
^abCalogeropoulou T, Avlonitis N, Minas V, Alexi X, Pantzou A, Charalampopoulos I, Zervou M, Vergou V, Katsanou ES, Lazaridis I, Alexis MN, Gravanis A (2009). "Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity".J. Med. Chem.52 (21):6569–87.doi:10.1021/jm900468p.PMID19845386.
^abcdefghiBotsakis K, Mourtzi T, Panagiotakopoulou V, Vreka M, Stathopoulos GT, Pediaditakis I, Charalampopoulos I, Gravanis A, Delis F, Antoniou K, Zisimopoulos D, Georgiou CD, Panagopoulos NT, Matsokis N, Angelatou F (2017). "BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor".Neuropharmacology.121:140–157.doi:10.1016/j.neuropharm.2017.04.043.PMID28461162.S2CID5071762.
^Bennett JP, O'Brien LC, Brohawn DG (2016). "Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis".Biochem. Pharmacol.117:68–77.doi:10.1016/j.bcp.2016.08.001.PMID27498123.
